Studies show NKT cells, a unique lymphocyte subpopulation, are characterized by the coexpression of an invariant antigen receptor and NK receptors. Human NKT cells (Vα24-Jα18) are activated by a specific glycolipid antigen, in a CD1d-dependent manner. CD1d molecules are heterodimers, composed of a heavy polypeptide chain non-covalently associated with a 2-microglobulin, and have substantial structural similarity to major histocompatibility complex (MHC) class I proteins. After activation, NKT cells exhibit MHC-independent antitumor activity against tumor cells in vitro and in vivo through several mechanisms. Activated Vα24 NKT cells produce a high level of cytokines, such as IFN-γ, thereby bridging innate and adaptive immunity through the activation of other effector cells including dendritic cells (DC), NK cells, and CD8+ T cells. NKTs play a regulatory role in the immune system, thus they are attractive targets for immunotherapy.
At present, the most well studied CD1d-presented antigen is alpha-galactosylceramide (αGalCer, KRN-7000). It initially drew interest when extracts derived from the marine sponge, Agelas mauritianus, demonstrated novel anti-tumor properties. Kirin Beer pharmaceutical company (U.S. Pat. No. 5,849,716). This potent activity was later traced to a family of alpha-linked glycospingolipids (GSLs), from which αGalCer was structurally optimized. The GSLs consists of a sugar moiety alpha-linked to a ceramide which is formed by an amide bond of a fatty acid with a long chain base.
Upon activation by αGalCer, NKT cells release proinflammatory (Th1) and immunomodulatory (Th2) cytokine. The production of TH1 cytokines is thought to correlate with antitumor, antiviral/antibacterial, and adjuvant activities, whereas TH2 cytokine production is thought to subdue autoimmune diseases. αGalCer has been the subject of clinical trials for its anti-cancer potential, but it was terminated during phase I. The non-specific nature of the cytokine profile induced by αGalCer, both Th1 and Th2, makes it less effective as a therapeutic treatment. This interpretation has encouraged many groups to focus on the searching for compounds which increase the selectivity toward either the TH1 or TH2 cytokines response. Wong et al. have synthesized a series of glycolipids bearing aromatic groups on the acyl side chain and found these molecules to skew the cytokine release profile towards a TH1 response (J. Am. Chem. Soc. 2006, 128, 9022-9023. US 2007/0238871). In vivo experiment on mice with aggressive lung cancer tumors (TC1 cell line) and breast cancer tumors (4T1 cell line) have showed that the lung cancer-bearing mice treated with the new glycolipids had significantly prolonged survival time compared to those treated with αGalCer. In breast cancer-bearing mice, treatment with the new glycolipids inhibited the tumor growth rate by 75% of untreated group, as compared to 50% inhibition in mice treated with α-GalCer (Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 10299-10304).
Therefore, there is a need for efficient means for synthesis of alpha-glycosphingolipids, such as αGalCer compounds, as well as a need for synthesis of novel alpha-glycosphingolipid compounds with immunomodulatory effects.